Subtype-selective N-methyl-D-aspartate receptor antagonists:: Synthesis and biological evaluation of 1-(heteroarylalkynyl)-4-benzylpiperidines
Subtype-selective N-methyl-D-aspartate receptor antagonists:: Synthesis and biological evaluation of 1-(heteroarylalkynyl)-4-benzylpiperidines
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DOI：
10.1021/jm000023o
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发表时间：
2000-09-07
影响因子：
7.3
通讯作者：
Wise, LD
中科院分区：
文献类型：
--
作者：
Wright, JL;Gregory, TF;Wise, LD
4-[4-（4-苄基哌啶-1-基）丁-1-炔基]苯酚（8）和4-[3-（4-苄基哌啶-1-基）丙-1-炔基]苯酚（9）是有效的NR 1A/2B受体拮抗剂（IC 50值分别为0.17和0.10 μ M）。腹膜内给药，他们都加强了活动的左旋多巴在单侧6-羟基多巴胺损伤（6-OHDA）大鼠，帕金森氏病模型。然而，化合物9口服没有活性，可能是由于苯酚部分的快速首过代谢。苯酚被几个含有NH基团的双环杂环系统取代，作为H键供体，希望这些不太可能经历快速代谢。在一般情况下，吲哚，吲唑，苯并三唑，吲哚酮和靛红得到的类似物与较弱的NR 1A/2B活性比母体酚，而苯并咪唑啉酮和苯并咪唑啉酮得到等效或更有效的类似物。H-键供体和连接乙炔部分之间的帕拉排列的偏好被确认，并且丙炔连接优选丁炔连接。取代苄基或哌啶上的4-羟基对NR 1A/2B效力几乎没有影响;然而，4-羟基哌啶对NR 1A/2B受体的选择性与α-1肾上腺素能和多巴胺D2受体亲和力相比略有改善。从这项研究中，5-[3-（4-苄基哌啶-1-基）丙-1-炔基]-1，3-二氢苯并咪唑-2-酮（46 b）被鉴定为非常有效的选择性NR 1A/2B受体拮抗剂（IC 50值0.0053 μ M）。在以10和30 mg/kg口服给药后，46 b增强了L-DOPA在6-OHDA损伤大鼠中的作用，并且似乎具有改善的口服生物利用度，但与苯酚9相比脑渗透性较低。
4-[4-(4-Benzylpiperidin-1-yl)but-1-ynyl]phenol (8) and 4-[3-(4-benzylpiperidin-1-yl)prop-1-ynyl phenol (9) are potent NR1A/2B receptor antagonists (IC50 values 0.17 and 0.10 mu M, respectively). Administered intraperitoneally, they both potentiated the activity of L-DOPA in the unilaterally 6-hydroxydopamine-lesioned (6-OHDA) rat, a model of Parkinson's disease. However, compound 9 was not active orally, likely due to rapid first-pass metabolism of the phenol moiety. The phenol was replaced by several bicyclic heterocyclic systems containing an NH group to function as a H-bond donor in the hope that these would be less likely to undergo rapid metabolism. In general, indoles, indazoles, benzotriazoles, indolones, and isatins gave analogues with weaker NR1A/2B activity than the parent phenols, while benzimidazolones and benzimidazolinones gave equipotent or more potent analogues. The preference for a para arrangement between the H-bond donor and the linking acetylene moiety was confirmed, and a propyne link was preferred over a butyne link. Substitution on the benzyl group or a 4-hydroxyl group on the piperidine had little effect on NR1A/2B potency; however, 4-hydroxypiperidines demonstrated slightly improved selectivity for NR1A/2B receptors versus alpha-1 adrenergic and dopamine D2 receptor affinity. From this study, 5-[3-(4-benzylpiperidin-1-yl)prop-1-ynyl]-1,3-dihydrobenzo-imidazol-2-one (46b) was identified as a very potent, selective NR1A/2B receptor antagonist (IC50 value 0.0053 mu M). After oral administration at 10 and 30 mg/kg, 46b potentiated the effects of L-DOPA in the 6-OHDA-lesioned rat and seemed to have improved oral bioavailability but lower brain penetration compared to phenol 9.